Tiffany Polzin, “Molecular Mechanisms of Estradiol/TrkB Interactions in the Dorsal Hippocampus of Female Mice”
Mentors: Karyn Frick & Kellie Gross, Psychology
Our laboratory has previously demonstrated that 17β-estradiol (E2) enhances memory consolidation in both object placement (OP) and object recognition (OR) tasks, but the molecular mechanisms underlying these effects have yet to be fully uncovered. Brain derived neurotrophic factor (BDNF) is a positive regulator of memory in the hippocampus via activation at its receptor TrkB. Although BDNF is known to interact with E2, the role of TrkB activation in the memory-enhancing effects of E2 has yet to be understood. In previous Frick lab experiments, intracranially cannulated ovariectomized female C57BL/6 mice were infused with vehicle or a non-memory impairing dose of ANA-12, a TrkB antagonist, into the dorsal hippocampus (DH), and either vehicle or E2 in the dorsal third ventricle. OR and OP memory were tested either 24 or 48 hours later. ANA-12 blocked the memory-enhancing effects of E2, suggesting that BDNF/TrkB signaling is needed for E2 to enhance object recognition and spatial memory consolidation. The present study harvested the brains of these mice and then used western blotting and PCR to measure effects of vehicle and E2 on protein and mRNA in the dorsal hippocampus. We found that E2 increased TrkB phosphorylation and BDNF mRNA in the dorsal hippocampus 4 hours after E2 treatment, suggesting that E2 activates TrkB/BDNF signaling. We next strived to uncover how E2 interacts with TrkB interacts to influence memory, and focused on the NMDA receptor subunit, NR2B, because E2 increases NR2B phosphorylation. We discovered that E2 increased NR2B phosphorylation, and this phosphorylation was blocked by ANA-12, suggesting a key role for NR2B phosphorylation in the interactions between E2 and TrkB. These findings provide new information on the molecular mechanisms through which E2 modulates hippocampal memory consolidation. Current work aims to uncover how E2-induced TrkB activation results in NR2B phosphorylation and the implications of this on memory.
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